Individuals who generate especially vigorous (but usually hidden) regulatory responses to an initial drug challenge can appear to be initially insensitive to the drug based on summative outcome measures. Such individuals are vulnerable to acquiring hyperactive response(s) over repeated drug exposures, putting them at increased risk to escalate drug use and develop drug addiction. The allostatic model of addiction posits that drug-induced allostatic changes cause the growth of hyper-responsive and/or otherwise dysregulated responses that promote the development of addiction; i.e., an allostatic state motivates escalating drug use, creating a vicious cycle characterized by loss of control and compulsive drug-taking. While only a modest percentage of drug-exposed individuals become addicted, the aggregate costs to society are immense. Thus, understanding the causal mechanisms responsible for individual differences in addictive vulnerability has high priority. We have found that individual variation in initial drug sensitivity predicts future drug tolerance, drug self-administration, and the transition to allostatic dysregulation. The R21 phase proposes to develop a novel live-in ethanol-vapor exposure chamber for rats that also can be used for ethanol vapor self-administration. Specific Aim 1 (SA1) builds the apparatus and tests its reliability to deliver a specified ethanol vapor concentration and clear it from the chamber. SA2 will measure the relationship between inhaled ethanol vapor concentration and blood ethanol levels and validate the functionality of the apparatus by assessing individual differences in initial sensitivity, acquisition of self-administration, and degree of chronic tolerance development. SA3 validates the use of alcohol vapor in a live-in thermal gradient apparatus. In the R33 phase, SA4 tests the hypothesis that individual differences in initial sensitivity to alcohol reliably predict persistent differences in alcohol vapor self-administration. SA5 tests the hypothesis that individual differences in initial sensitivity to alcohol predict the development of allostatic dysregulation over repeated alcohol exposures in a thermal gradient. SA6 tests the hypothesis that a non-drug challenge can substitute for an initial alcohol challenge in identifying reliable inter-individual response variation that predicts the development of allostatic dysregulation. The translational impact of our research will be enhanced if an individual's likelihood of developing allostasis could be assessed without requiring an initial drug challenge. The proposed studies will provide robust and unbiased results through the use of rigorous experimental designs and methods that include continuous measurements of variables such as behavioral and metabolic-rate responses during naturalistic or alcohol-induced regulatory challenges. This innovative research is based on a strong conceptual framework and is of theoretical and practical importance for advancing our knowledge and understanding of the mechanisms underlying addictive vulnerability.